Abstract
BackgroundCD44 has long been associated with glioma invasion while, more recently, CD155 has been implicated in playing a similar role. Notably, these two receptors have been shown closely positioned on monocytes.Methods and FindingsIn this study, an up-regulation of CD44 and CD155 was demonstrated in established and early-passage cultures of glioblastoma. Total internal reflected fluorescence (TIRF) microscopy revealed close proximity of CD44 and CD155. CD44 antibody blocking and gene silencing (via siRNA) resulted in greater inhibition of invasion than that for CD155. Combined interference resulted in 86% inhibition of invasion, although in these investigations no obvious evidence of synergy between CD44 and CD155 in curbing invasion was shown. Both siRNA-CD44 and siRNA-CD155 treated cells lacked processes and were rounder, while live cell imaging showed reduced motility rate compared to wild type cells. Adhesion assay demonstrated that wild type cells adhered most efficiently to laminin, whereas siRNA-treated cells (p<0.0001 for both CD44 and CD155 expression) showed decreased adhesion on several ECMs investigated. BrdU assay showed a higher proliferation of siRNA-CD44 and siRNA-CD155 cells, inversely correlated with reduced invasion. Confocal microscopy revealed overlapping of CD155 and integrins (β1, αvβ1 and αvβ3) on glioblastoma cell processes whereas siRNA-transfected cells showed consequent reduction in integrin expression with no specific staining patterns. Reduced expression of Rho GTPases, Cdc42, Rac1/2/3, RhoA and RhoB, was seen in siRNA-CD44 and siRNA-CD155 cells. In contrast to CD44-knockdown and ‘double’-knockdown cells, no obvious decrease in RhoC expression was observed in CD155-knockdown cells.ConclusionsThis investigation has enhanced our understanding of cell invasion and confirmed CD44 to play a more significant role in this biological process than CD155. Joint CD44/CD155 approaches may, however, merit further study in therapeutic targeting of infiltrating glioma cells.
Highlights
Local invasion of the brain by neoplastic glial cells is arguably the most significant biological feature of primary brain tumours which hinders successful therapy [1]
This investigation has enhanced our understanding of cell invasion and confirmed CD44 to play a more significant role in this biological process than CD155
Expression of CD44 and CD155 on the surface of normal astrocytes and glioblastoma multiforme (GBM) cells were analysed by ICC and flow cytometry
Summary
Local invasion of the brain by neoplastic glial cells is arguably the most significant biological feature of primary brain tumours which hinders successful therapy [1]. Glioma cell invasion of surrounding brain tissue frequently precludes complete surgical resection. Integrins, consisting of a and b subunits [6], are key molecules on the cell surface which facilitate ECM/CAMs interaction and binding. Integrins play their mediating role in adhesive events during malignant transformation, tumour growth and progression, invasion and metastasis by providing a physical transmembrane link between the ECM and underlying cytoskeletal elements, which results in transduction of bidirectional signals across the cell membrane [4]. CD44 has long been associated with glioma invasion while, more recently, CD155 has been implicated in playing a similar role These two receptors have been shown closely positioned on monocytes
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